Update on Drug-Drug Interactions A Scientific Perspective药物间相互作用的科学的角度更新PPT文档格式.ppt
- 文档编号:4118395
- 上传时间:2023-05-02
- 格式:PPT
- 页数:26
- 大小:172KB
Update on Drug-Drug Interactions A Scientific Perspective药物间相互作用的科学的角度更新PPT文档格式.ppt
《Update on Drug-Drug Interactions A Scientific Perspective药物间相互作用的科学的角度更新PPT文档格式.ppt》由会员分享,可在线阅读,更多相关《Update on Drug-Drug Interactions A Scientific Perspective药物间相互作用的科学的角度更新PPT文档格式.ppt(26页珍藏版)》请在冰点文库上搜索。
SpecificcommentsontheconceptpaperStudydesignsTablesSpecificcommentsonthequestionstothecommittee,吁嫌宾撅父嘉添甄叼达弯坐缔纸诅如类怕膨密孟循贴焉陌应傻勘枕琅枝讶UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新,3,ApproachtoAssessingDrugInteractions,Whatistheprimaryquestion?
Should(andhowshould)thedoseofthesubstratedrugbeadjustedinthepresenceoftheinteractingdrug?
WhichDDItostudyandhowtoanswer?
Wearemovingfromthe“past”wherechoicewaslargelydeterminedbythelikelihoodofco-administration/clinicalconsequencesofaninteractionGoal:
science-drivenapproach(wherefeasible)PreclinicalinvitrostudiestodetermineinvivostudiestoconductinvivostudiesusingprobesubstratesRobuststudydesignsarecriticalBut:
ThereareareaswherethescienceisevolvingNecessarytools(e.g.probes)arestilllacking,邓彤溢丽摸朱碑散侦探奈碘栈列改旬木休女荡荧滨嘘膝浇蔫韩妻饯缸锦霜UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新,4,ApproachtoAssessingDrugInteractions
(2),Howdoweusethedatatoanswertheprimaryquestion?
Pre-specifiedcriteriatocomparethePK(orPD)measuresforthesubstratedruginthepresenceoftheinteractingdrugBasedonthesafetyandefficacyprofileofthesubstratedrug(e.g.,therapeuticindex),clinicalcontextoftheuseofthedrug,andconcentration-responsedataforthesubstrateOftennotclearly“positive”or“negative”FortheNCE,oftendataislimitedConcentrationresponseinfooftenprimarilyforefficacyForprobesubstrates,stillnotmuchconsensus(thoughmuchprogressforCYP3A4inhibition)Induction,inparticular,hasbeenproblematictointerpret,热滋买巳曙超篆速粘紧螟恨锑痴粗绅樱春跺杉具货双酬嘎感甥轻犊响犀缉UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新,5,AreasofAgreement,IntegratedandscientificapproachClarityonCYPinteractionsveryusefulEspecially,invitro/invivocorrelationsInvitro/invivoclarityonsubstrates,inhibitors,inducersUseofPKinpoormetabolizers(whereappropriate)RobuststudydesignsUsefulandconsistentlabelinglanguageStillsomediscussionneededonhowtolabel“moderateinhibitors”andhowtodefine“sensitive”CYPsubstratesThe“devilisinthedetails”.,扭袍伞埔厕瓢叮灾容兼谋擂狮棕咎靴昔轩困焕售待澄墅桑技漱坡润种傍囤UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新,6,Science-drivenapproach:
wherewearetodaywithinvitropredictionsofinvivoDDIs?
Readyfor“prime-time”:
CYPinhibition(1A2,2C9,2C19,2D6,3A4)Almostreadyfor“primetime”:
P-glycoprotein(P-gp)?
UGT1A1(andotherUGTs)CYP2B6andCYP2C8CYPinductionNotreadyfor“primetime”:
MosttransportersMultiplepathsofinhibition(interactingdrugs/genetics/impairedclinicalconditions),俄笺健藐市狼恋爷媚饿舀优伟夹罩誉六汀莽汤焰寸睡斧顶锄烷龚增职它穴UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新,7,Induction,Threemajorconcernsforinduction:
Reductionintherapeuticefficacy(mostcommon)Autoinduction(time-dependentPK)Imbalancebetweentoxification/detoxificationDose-andtime-dependentDependentalsoonclearanceandrouteofadministrationAconcernbothwithinitiationanddiscontinuationofinteractingdrug,炼山曹落轴磨卷碘休绊葡唤促习疫麓艰惰膘膀搅芽缘低侮眨醋铭至吠呀揖UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新,8,HowtoassessforthepotentialforCYPinduction?
AnimalmodelsPreviously,short-term,highdosestudiesinrodentsPoorpredictor?
Speciesdifferencesininduction?
InvitromodelshPXRassayPrimarycultureofhumanhepatocytesEnzymeactivitymRNAClearlyveryhelpfulinselectionofdrugcandidatesButisquantitativeinvitro/invivopredictionpossible?
阜国叭恋匹念擅重平借经给辽答诊母敬怂赢戊轧肇凌察境刮显通敖呢甲哄UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新,9,Factorsthatcomplicatetheinvitro/invivoextrapolation,InterindividualvariabilityInvitrovariabilityRifampinfold-increasesonCYP3A4protein:
3-24InvivovariabilityRifampinfold-decreasesonAUCofmidazolaminhumans:
11-55EffectofplasmaproteinbindingonCYPinductionInvolvementofmultiplemechanismsinCYPinduction,烧菠恢腹就痉羽翰岩项佑闯幻龄陋嗜势冒与跌周摊爷花频粕孩弄硫西迪懈UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新,10,Somehypotheticalexamples,1Percentof10uMrifampincontrolwithdrugtestedat1and10uM;
2Cmaxinhumansatclinicaldose,毙升平炬忿红撤椽亭侮中撼吃枯帅温罢烦王醒猛仙豪涝硼渐浚劣故裕藻铂UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新,11,Induction(cont),Sowhichneedaninvivostudy?
Conclusion:
Atpresent,wecanonlypredictalikelihoodofCYPinduction,e.g.“highlypossible”or“lesslikely”Additionalclinicaldatasometimeshelp:
Evidenceofautoinduction,orevidenceoflessaccumulationthanexpectedHowdoweinterpretaninvivostudy?
Lessconsensusonuseofprobesubstratesandtheir“clinicalinterpretation”e.g.,howmuchdecreaseinmidazolamisclinicallyrelevant?
Howdoweextrapolatetoothersubstratedrugs?
殴氯恃躺庞崖粉眠烤苗龋庙泌林砂美檀膊卉答渺辗棠悠叙庚骋敌限咋抄心UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新,12,InductionofCYP3A4:
effectonoralmidazolamAUC(PercentofBaselineexposure),跺辖辕查郸滑沽馅瘁遭棘页拘亭瘤惑子尖铱聊律楼凋匹蹬兄逞昆邑涨溃椒UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新,13,InductionofCYP3A4:
effectonoralmidazolamAUC,赡潘鞋伎锁锰妒发撂聘刃尤陀秤寥屿券零隅剩本萎托牡逐沽权廉矛毯标庸UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新,14,InductionofCYP3A4:
effectonoralmidazolamAUC,贬癣姿瘁杏讣玩史榜秦吩吩徒搁迸追佬肠市肝驮农噎犁峦共讣残眉烩毫汕UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新,15,Transporters,Morerecently,roleoftransportershasbeenrecognizedtoagreaterextent,andsomeclearexamplesoftransporter-mediateddruginteractionsexistParticularly,theunderstandingofP-glycoproteinhasadvancedgreatlyBut,theinvitromethodsarenotstandardizedand/orarenotreadilyavailableAquantitativeinvitropredictionofinvivorelevancemaynotbepossibleatthispointComplicatedbythefactthattransportersalsoaffectabsorption,tissuedistribution,andexcretion,续俏鲸激框液腰江陈斗欧遁遗廷倍咸烟靳齐涛砸财倒禾袍殃秸讨矽塞郊篆UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新,16,P-glycoprotein,Broadtissuedistribution:
GI,liver,renal,brain,etc.Potentialrolesindrugabsorption,distribution,andexcretionSomeimportantinvitromethodologiesexist,butTransgenicmdrknockoutmiceareapowerfultool,butmanycaveats(e.g.,human/rodentdifferences)Invitrotoolsarebecomingmoresophisticated,buttheinteractionsbetweenP-gpsubstratesdoesnotalwaysfollowsimplekineticsOverlappingsubstratesbetweenP-gpandCYP3A4,andmanyinhibitorsaffectbothToolsaremostusefultoidentifyP-gpsubstratesInvitro/invivocorrelationsarestilllimited,睬聊膳苹舌饥疯内春萌竣垂侮盾风帝坯藉恤旬舱颠光俊痢穴凶挺槐绅给丑UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新,17,P-glycoprotein(cont),WhatmightaclinicalpharmacologistreceiveasanevaluationofthepotentialforP-gpmediateddruginteractions?
“BidirectionaltransportwasevaluatedacrossmonolayersofLLC-PK1cellsoverexpressinghuman(MDR1)andmouse(mdr1a)P-gp.DrugF,atwasnotasubstrateforhumanMDR1(B/Aratio=1.7),butwasamoderatelygoodsubstrateformousemdr1a(B/Aratio=10.1).”“BrainpenetrationwasevaluatedinvivoinP-gpdeficientandP-gpcompetentmice.ComparisonofbrainconcentrationsindicatesthatP-gpactivityresultedina6-foldreductioninAUCinthebrain;
theAUCratiosbetweenbrainandplasmawere1.0and0.17inP-gpdeficientandcompetentmice,respectively.”Whatshouldtheapproachbe?
Ifaninvivostudyisindicated:
ForassessingP-gpinhibitors,digoxinisasuitableprobeOtherprobeP-gpsubstratesarelessthanideal,赔煤灵戏量撅宜唉堪副豫喧痘凛糊宅鹿从脯寝岗晌个凤吨楼枉窒右朝疆兹UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新,18,P-gptransporterbasedinteraction,IfaNMEisasubstrateforP-gpandCYP3A,aclinicalstudywithadualinhibitor(e.g.,ritonavir)maybeappropriate,Ritonavir,Ketoconazole200mg,Erythromycin,Indinavir,VardenafilAUC(co-administration),CourtesyofShiew-MeiHuang,2004,琼鲜帕熄蜀喀栏杠与吸嵌缄掣川净写湿炙旺谋赡澈渊嚷留宜似闪蘑竞糕堂UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新UpdateonDrug-DrugInteractiosAScientificPerspective药物间相互作用的科学的角度,更新,19,P-gptransporterbasedinteraction,IfaNMEisasubstrateforP-gpandNOTCYP3A4,aclinicalstudywithaP-gpinhibitor(e.g.,cyclosporine,verapamil)maybeappr
- 配套讲稿:
如PPT文件的首页显示word图标,表示该PPT已包含配套word讲稿。双击word图标可打开word文档。
- 特殊限制:
部分文档作品中含有的国旗、国徽等图片,仅作为作品整体效果示例展示,禁止商用。设计者仅对作品中独创性部分享有著作权。
- 关 键 词:
- Update on Drug-Drug Interactions Scientific Perspective药物间相互作用的科学的角度,更新 Drug Perspec
链接地址:https://www.bingdoc.com/p-4118395.html